Neuronal calcium sensor (NCS) proteins regulate signal transduction and are highly conserved from yeast to humans. NCS homolog in fission yeast (Ncs1p) is essential for cell growth under extreme Ca(2+) conditions. Ncs1p expression increases approximately 100-fold when fission yeast grows in high extracellular Ca(2+) (>0.1 M). Here, we show that Ca(2+)-induced expression of Ncs1p is controlled at the level of transcription. Transcriptional reporter assays show that ncs1 promoter activity increased 30-fold when extracellular Ca(2+) was raised to 0.1 M and was highly Ca(2+)-specific. Ca(2+)-dependent transcription of ncs1 is abolished by the calcineurin inhibitor (FK506) and by knocking out the calcineurin target, prz1. Thus, Ca(2+)-induced expression of Ncs1p is linked to the calcineurin/prz1 stress response. The Ca(2+)-responsive ncs1 promoter region consists of 130 nucleotides directly upstream from the start codon and contains tandem repeats of the sequence, 5'-caact-3', that binds to Prz1p. The Ca(2+)-sensitive ncs1Delta phenotype is rescued by a yam8 null mutation, suggesting a possible interaction between Ncs1p and the Ca(2+) channel, Yam8p. Ca(2+) uptake and Ncs1p binding to yeast membranes are both decreased in yam8Delta, suggesting Ca(2+)-induced binding of Ncs1p to Yam8p results in channel closure. We propose that Ncs1p promotes Ca(2+) tolerance in fission yeast, in part by cytosolic Ca(2+) buffering and perhaps by negatively regulating the Yam8p Ca(2+) channel.